Abstract
Activin E, encoded by INHBE, is a TGF-ß family growth factor. Secreted by hepatocytes under high hepatic triglyceride and free fatty acid levels, it acts on adipocytes through ALK7 to inhibit lipolysis and mitigate hepatic lipid overload. Preclinical data prove INHBE-targeted RNAi outperforms existing anti-obesity drugs by cutting fat mass without muscle loss, and the leading candidate has entered Phase 1/2a trials.
Biocytogen constructed B-hlNHBE humanized mice that only express human INHBE, supporting INHBE-related pre- clinical research. Exons 1-2 of the mouse Inhbe gene, which encode the entire molecule (from ATG start codon to STOP codon), including the 3' UTR, were replaced with their human counterparts. The promoter and 5' UTR regions of the mouse gene were retained. Human INHBE expression is driven by the endogenous mouse Inhbe promoter, while transcription and translation of the mouse Inhbe gene are disrupted.
To establish the diet-induced obesity (DIO) model, C57BL/6 and B-hlNHBE mice (male, 7 weeks old) were fed a high-fat diet (60 kcal% fat) for 12 weeks to induce obesity. To evaluate the in vivo efficiency of RNAi therapy, DIO B-hlNHBE mice were treated weekly with an siRNA drug targeting INHBE (provided by the client; synthesized based on a patent) at a dose of 9 mpk subcutaneously.
The growth curve of DIO B-hlNHBE mice closely resembled that of DIO C57BL/6 mice. In the in vivo efficiency test, siRNA targeting INHBE inhibited body weight gain in DIO B-hlNHBE mice compared to the saline-treated group. Treatment with siRNA targeting INHBE also resulted in fat mass loss while preserving lean mass.
B-hlNHBE mice stably express functional human INHBE, representing a reliable in vivo model for evaluating anti-obesity and muscle-protective INHBE RNAi therapeutics.
